This invention relates to novel substituted pyrrole compounds useful for Inflammatory Diseases.
The structure and physical properties of human non-pancreatic secretory phospholipase A2 (hereinafter called, xe2x80x9csPLA2xe2x80x9d) has been thoroughly described in two articles, namely, xe2x80x9cCloning and Recombinant Expression of Phospholipase A2 Present in Rheumatoid Arthritic Synovial Fluidxe2x80x9d by Seilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter, Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of April 5, pp. 5335-5338, 1989; and xe2x80x9cStructure and Properties of a Human Non-pancreatic Phospholipase A2xe2x80x9d by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of April 5, pp. 5768-5775, 1989; the disclosures of which are incorporated herein by reference.
It is believed that sPLA2 is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids. Thus, it is important to develop compounds which inhibit sPLA2 mediated release of fatty acids (e.g., arachidonic acid). Such compounds would be of value in general treatment of conditions induced and/or maintained by overproduction of sPLA2; such as sepsis or rheumatoid arthritis.
It is desirable to develop new compounds and treatments for sPLA2 induced diseases.
This invention provides novel substituted pyrrole compounds having potent and selective effectiveness as inhibitors of mammalian sPLA2.
This invention is also the use of novel substituted pyrrole compounds useful in the treatment and prevention of Inflammatory Diseases.
This invention is also the use of novel substituted pyrrole compounds to inhibit mammalian sPLA2 mediated release of fatty acids.
This invention is also a pharmaceutical composition containing any of the substituted pyrrole compounds of the invention.
The term, xe2x80x9cInflammatory Diseasesxe2x80x9d refers to diseases such as inflammatory bowel disease, sepsis, septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, spondylarthropathris, ankylosing spondylitis, Reiter""s syndrome, psoriatic arthropathy, enterapathric spondylitis, Juvenile arthropathy or juvenile ankylosing spondylitis, Reactive arthropathy, infectious or post-infectious arthritis, gonoccocal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with xe2x80x9cvasculitic syndromesxe2x80x9d, polyarteritis nodosa, hypersensitivity vasculitis, Luegenec""s granulomatosis, polymyalgin rheumatica, joint cell arteritis, calcium crystal deposition arthropathris, pseudo gout, non particular rheumatism, bursitis, tenosynomitis, epicondylitis (tennis elbow), carpal tunnel syndrome, repetitive use injury (typing), miscellaneous forms of arthritis, neuropathic joint disease (charco and joint), hemarthrosis (hemarthrosic), Henoch-Schonlein Purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, arthritis associated with certain diseases, surcoilosis, hemochromatosis, sickle cell disease and other hemoglobinopathries, hyperlipoproteineimia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behat""s Disease, systemic lupus erythrematosis, or relapsing polychondritis and related diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula I in an amount sufficient to inhibit sPLA2 mediated release of fatty acid and to thereby inhibit or prevent the arachidonic acid cascade and its deleterious products.
The term, xe2x80x9csubstituted pyrrole nucleusxe2x80x9d as used herein refers to a nucleus (having numbered positions) with the structural formula (X): 
wherein A is O, NR, SO2, SO, or S.
The substituted pyrrole compounds of the invention employ certain defining terms as follows:
The term, xe2x80x9calkylxe2x80x9d by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, sec-butyl, n-pentyl, and n-hexyl.
The term, xe2x80x9calkenylxe2x80x9d employed alone or in combination with other terms means a straight chain or branched monovalent hydrocarbon group having the stated number range of carbon atoms, and typified by groups such as vinyl, propenyl, crotonyl, isopentenyl, and various butenyl isomers.
The term, xe2x80x9chydrocarbylxe2x80x9d means an organic group containing only carbon and hydrogen.
The term, xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo, or iodo. The term, heterocyclic radical, refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nuclei having 5 to 14 ring atoms and containing from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur. Typical heterocyclic radicals are pyrrolyl, pyrrolodinyl, piperidinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, indazolyl, imidazo(1.2-A)pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pyridinyl, dipyridylyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl,morpholino, thiomorpholino, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, oxacanyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrahydrothiopheneyl, pentamethylenesulfadyl, 1,3-dithianyl, 1,4-dithianyl, 1,4-thioxanyl, azetidinyl, hexamethyleneiminium, heptamethyleneiminium, piperazinyl and quinoxalinyl.
The term, xe2x80x9ccarbocyclic radicalxe2x80x9d refers to radicals derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered organic nucleus whose ring forming atoms (other than hydrogen) are solely carbon atoms. Typical carbocyclic radicals are cycloalkyl, cycloalkenyl, phenyl, spiro[5.5]undecanyl, naphthyl, norbornanyl, bicycloheptadienyl, toluyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, dibenzylyl and related dibenzylyl homologues represented by the formula (a): 
where n is a number from 1 to 8.
The terms, xe2x80x9cnon-interfering substituentxe2x80x9d, and xe2x80x9cnon-interfering groupxe2x80x9d refer to radicals suitable for substitution at positions 4, 5, 6 and/or 7 of the substituted pyrrole nucleus and on other nucleus positions or substituents (as hereinafter described for Formula I), and radicals suitable for substitution on the heterocyclic radical and carbocyclic radical as defined above. Illustrative non-interfering radicals are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C1-C8 alkoxy, C2-C8 alkenyloxy, C2-C8 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C2-C12 alkylthiocarbonyl, C1-C8 alkylsulfinyl, C1-C8 alkylsulfonyl, C2-C8 haloalkoxy, C1-C8 haloalkylsulfonyl, C2-C8 haloalkyl, C1-C8 hydroxyalkyl, xe2x80x94C(O)O(C1-C8 alkyl), xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(C1-C8 alkyl), benzyloxy, phenoxy, phenylthio, xe2x80x94(CONHSO2R), xe2x80x94CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, xe2x80x94(CH2)nxe2x80x94CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiocarbonyl, and carbonyl; where n is from 1 to 8 and R is C1-C8 alkyl.
The term, xe2x80x9corganic substituentxe2x80x9d refers to a monovalent radical consisting of carbon and hydrogen with or without oxygen, nitrogen, sulfur, halogen, or other elements. Illustrative organic substituents are C1-C8 alkyl, aryl, C7-C14 aralkyl, C7-C14 alkaryl, C3-C8 cycloalkyl, C1-C8 alkoxyalkyl and these groups substituted with halogen, xe2x80x94CF3, xe2x80x94OH, C1-C8 alkyl, amino, carbonyl, and xe2x80x94CN.
The term xe2x80x9csubstituted groupxe2x80x9d is an organic group substituted with one or more non-interfering substituents.
The term, xe2x80x9c(acidic group)xe2x80x9d means an organic group which when attached to a substituted pyrrole nucleus at positions 4 or 5, through suitable linking atoms (hereinafter defined as the xe2x80x9cacid linkerxe2x80x9d), acts as a proton donor capable of hydrogen bonding. Illustrative of an (acidic group) are the following:
-5-tetrazolyl, 
where n is 1 to 8, R80 is a metal or C1-C8 and R81 is an organic substituent or xe2x80x94CF3.
The words, xe2x80x9cacid linkerxe2x80x9d refer to a divalent linking group symbolized as, xe2x80x94(La)xe2x80x94, which has the function of joining the 4 or 5 position of the substituted pyrrole nucleus to an acidic group in the general relationship: 
The words, xe2x80x9cacid linker lengthxe2x80x9d, refer to the number of atoms (excluding hydrogen) in the shortest chain of the linking group xe2x80x94(La)xe2x80x94 that connects the 4 or 5 position of the substituted pyrrole nucleus with the acidic group. The presence of a carbocyclic ring in xe2x80x94(La)xe2x80x94 counts as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a benzene or cyclohexane ring in the acid linker counts as 2 atoms in calculating the length of xe2x80x94(La)xe2x80x94. Illustrative acid linker groups are; 
wherein, groups (a), (b), and (c) have acid linker lengths of 5, 7, and 2, respectively.
The term, xe2x80x9cN-hydroxyfunctional amide groupxe2x80x9d is represented by the formula: 
wherein,
R4a is selected from the group consisting of OH, (C1-C6)alkoxy, and aryloxy; and
wherein R4b is hydrogen or an organic substituent selected from the group consisting of C1-C8 alkyl, aryl, C7-C14 aralkyl, C7-C14 alkaryl, C3-C8 cycloalkyl, C1-C8 alkoxyalkyl and these groups substituted with halogen, xe2x80x94CF3, xe2x80x94OH, C1-C8 alkyl, amino, carbonyl, and xe2x80x94CN.
The phrase, xe2x80x9cN -hydroxyfunctional amide linkerxe2x80x9d refers to a divalent linking group symbolized as, xe2x80x94(Lh)xe2x80x94, which has the function of joining the 4 position of the substituted pyrrole nucleus to an N-hydroxyfunctional amide group in the general relationship: 
The words, xe2x80x9cN-hydroxyfunctional amide linker lengthxe2x80x9d, refer to the number of atoms (excluding hydrogen) in the shortest chain of the linking group xe2x80x94(Lh)xe2x80x94 that connects the 4 position of the substituted pyrrole nucleus with the N-hydroxyfunctional amide group. The presence of a carbocyclic ring in xe2x80x94(Lh)xe2x80x94 counts as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a benzene or cyclohexane ring in the N-hydroxyfunctional amide linker counts as 2 atoms in calculating the length of xe2x80x94(Lh)xe2x80x94. Illustrative N-hydroxyfunctional amide linker groups are; 
wherein, groups (a), (b), and (c) have N-hydroxyfunctional amide linker lengths of 5, 7, and 2, respectively.
The term, xe2x80x9cacylamino acid groupxe2x80x9d is represented by the formula: 
wherein R4c is selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl and aryl, xe2x80x94CF3; and wherein NR4d is an amino acid residue of either a natural or unnatural amino acid with the nitrogen atom being part of the amino group of the amino acid. A typical amino acid is selected from the group comprising isoleucine, valine, phenylalanine, aspartic acid, leucine, glycine, asparagine, cystein, glutamine, glutamic acid, histidine, lysine, methionine, serine, threonine, tryptophan, tyrosine and derivatives thereof. Contemplated within the definition of amino acid are l-proline, d-proline and derivatives thereof. Also contemplated within the definition of amino acids are peptides, polypeptides and derivatives thereof. The term, xe2x80x9camino acid residuexe2x80x9d refers to the portion of the amino acid group coupled at the nitrogen atom of the amino terminus. It is the amino acid less a hydrogen atom from the amino terminus. It is further illustrated as used herein for the amino acid alanine attached at the nitrogen atom as shown below: 
The words, xe2x80x9cacylamino acid linkerxe2x80x9d refer to a divalent linking group symbolized as, xe2x80x94(Lc)xe2x80x94, which has the function of joining the 4 position of the substituted pyrrole nucleus to an acylamino acid group in the general relationship: 
The words, xe2x80x9cacylamino acid linker lengthxe2x80x9d, refer to the number of atoms (excluding hydrogen) in the shortest chain of the linking group xe2x80x94(Lc)xe2x80x94 that connects the 4 position of the substituted pyrrole nucleus with the acidic group. The presence of a carbocyclic ring in xe2x80x94(Lc)xe2x80x94 counts as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a benzene or cyclohexane ring in the acid linker counts as 2 atoms in calculating the length of xe2x80x94(Lc)xe2x80x94. Illustrative acylamino acid linker groups are; 
wherein, groups (a), (b), and (c) have acylamino acid linker lengths of 5, 7, and 2, respectively.
As used herein the terms xe2x80x9cgroupxe2x80x9d, xe2x80x9cradicalxe2x80x9d or xe2x80x9cfragmentxe2x80x9d are synonymous and are intended to indicate functional groups or fragments of molecules attachable to a bond or other fragments of molecules. For example acetamide group represent the acetamide fragment or radical. Structures of groups, radicals or fragments unattached to the substituted pyrrole nucleus have been drawn to show the first line as a connecting bond only, Thus, the group 
indicates the acetamide radical not the propanamide radical unless otherwise indicated.
The term, xe2x80x9caminexe2x80x9d, includes primary, secondary and tertiary amines.
The terms, xe2x80x9cmammalxe2x80x9d and xe2x80x9cmammalianxe2x80x9d include human and domesticated quadrupeds.
The term, xe2x80x9calkylene chain of 1 or 2 carbon atomsxe2x80x9d refers to the divalent radicals, xe2x80x94CH2xe2x80x94CH2xe2x80x94 and xe2x80x94CH2xe2x80x94.
The term xe2x80x9cgroup containing 1 to 4 non-hydrogen atomxe2x80x9d refers to relatively small groups which form-substituents at the 2 position of the substituted pyrrole nucleus, said groups may contain non-hydrogen atoms alone, or non-hydrogen atoms plus hydrogen atoms as required to satisfy the unsubstituted valence of the non-hydrogen atoms, for example; (i) groups absent hydrogen which contain no more than 4 non-hydrogen atoms such as xe2x80x94CF3, xe2x80x94Cl, xe2x80x94Br, xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO3; and (ii) groups having hydrogen atoms which contain less than 4 non-hydrogen atoms such as xe2x80x94CH3, xe2x80x94C2H5, and xe2x80x94CHxe2x95x90CH2.
The term xe2x80x9coxime amidexe2x80x9d means the radical, xe2x80x94C(xe2x95x90NOR)xe2x80x94C(O)NH2 wherein R is alkyl, aryl, alkylaryl or arylalkyl.
The term xe2x80x9cthio-oxime amidexe2x80x9d means the radical xe2x80x94C(xe2x95x90NOR)xe2x80x94C(S)xe2x80x94NH2 wherein R is alkyl, aryl, alkylaryl or arylalkyl.
The term xe2x80x9cspiro[5.5]undecanylxe2x80x9d refers to the group represented by the formula; 
The present invention provides novel classes of substituted pyrrole compounds useful as sPLA2 inhibitors for the treatment of Inflammatory Diseases. Classes of substituted pyrrole compounds of this invention include substituted pyrrole glyoxylamide derivatives, substituted pyrrole-3-oxime amide derivatives and substituted pyrrole acetamide derivatives. The compounds of the invention have the general formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof; 
wherein;
A is O, S, SO, SO2, or NR; and wherein R is a non-interfering substituent;
R1 is selected from groups (a), (b), and (c) wherein;
(a) is C7-C20 alkyl, C7-C20 haloalkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
(b) is a member of (a) substituted with one or more independently selected non-interfering substituents; or
(c) is the group xe2x80x94(L1)xe2x80x94R11; where, xe2x80x94(L1)xe2x80x94 is a divalent linking group of 1 to 8 atoms and where R11 is a group selected from (a) or (b),
R2 is hydrogen, or a group containing 1 to 4 non-hydrogen atoms plus any required hydrogen atoms;
R3 is xe2x80x94(L3)xe2x80x94 Z, where xe2x80x94(L3)xe2x80x94 is a divalent linker group selected from a bond or a divalent group selected from: 
xe2x80x83and Z is selected from an amide including acetamide, oxime amide, oxime thioamide, glyoxylamide or a group represented by the formulae, 
xe2x80x83wherein X is oxygen or sulfur, Ra is independently selected from hydrogen, C1-C8 alkyl, aryl, C1-C8 alkaryl, C1-C8 alkoxy, aralkyl and xe2x80x94CN;
R4 is the group hydrogen, or the group xe2x80x94(La)xe2x80x94(acidic group); wherein xe2x80x94(La)xe2x80x94, is an acid linker having an acid linker length of 1 to 8;
or the group WR4e wherein W is O, S, or NH, and R4e is a non-interfering substituent;
or the group (Lc)xe2x80x94(acylamino acid group); wherein xe2x80x94(Lc)xe2x80x94, is an acylamino acid linker having an acylamino acid linker length of 1 to 8;
or the group xe2x80x94(Lh)xe2x80x94(N-hydroxyfunctional amide group); wherein xe2x80x94(Lh)xe2x80x94, is an N-hydroxyfunctional amide linker having an N-hydroxyfunctional amide linker length of 1 to 8;
R5 is selected from hydrogen, a non-interfering substituent, or the group, xe2x80x94(La)xe2x80x94(acidic group); wherein xe2x80x94(La)xe2x80x94, is an acid linker having an acid linker length of 1 to 8;
Preferred Subgroups of Compounds of Formula (I):
Preferred R1 Substituents:
A preferred subclass of compounds of formula (I) are those for which the substituent A is sulfur or oxygen. Most preferred are compounds of formula (I) wherein the substituent A is sulfur.
Another preferred subclass of compounds of formula (I) are those where for R1 the divalent linking group xe2x80x94(L1)xe2x80x94 is a group represented by any one of the following formulae (Ia), (Ib), (Ic), (Id), (Ie), or (If): 
where Q1 is a bond or any of the divalent groups (Ia), (Ib), (Ic), (Id), (Ie), and (If) and each R10 is independently hydrogen, C1-C8 alkyl, C1-C8 haloalkyl or C1-C8 alkoxy.
Particularly preferred as the linking group xe2x80x94(L1)xe2x80x94 of R1 is an alkylene chain of 1 or 2 carbon atoms, namely, xe2x80x94(CH2)xe2x80x94 or xe2x80x94(CH2xe2x80x94CH2)xe2x80x94.
The preferred group for R11 is a substituted or unsubstituted group selected from the group consisting of C5-C14 cycloalkyl, C5-C14 cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, toluyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (a); 
where n is a number from 1 to 8.
Particularly preferred are compounds wherein for R1 the combined group xe2x80x94(L1)xe2x80x94R11 is selected from the group consisting of 
where R12 is a radical independently selected from halo, C1-C8 alkyl, C1-C8 alkoxy, xe2x80x94Sxe2x80x94(C1-C8 alkyl), xe2x80x94Oxe2x80x94(C1-C8 alkyl) and C1-C8 haloalkyl where t is a number from 0 to 5 and u is a number from 0 to 4 is the group xe2x80x94(L1)xe2x80x94R11; where, xe2x80x94(L1)xe2x80x94 is a divalent linking group of 1 to 8 atoms and where R11 is a group selected from (a) or (b).
Preferred for R11 is xe2x80x94(CH2)mxe2x80x94R12 wherein m is an integer from 1 to 6, and R12 is (d) a group represented by the formula: 
wherein a, c, e, n, q, and t are independently an integer. from 0 to 2, R13 and R11 are independently selected from a halogen, C1 to C8 alkyl, C1 to C8 alkyloxy, C1 to C8 alkylthio, aryl, heteroaryl, and C1 to C8 haloalkyl, xcex1 is an oxygen atom or a sulfur atom, L5 is a bond, xe2x80x94(CH2)vxe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94CCxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94, v is an integer from 0 to 2, xcex2 is xe2x80x94CH2xe2x80x94 or (CH2)2xe2x80x94, xcex3 is an oxygen atom or a sulfur atom, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, r is an integer from 0 to 7, and u is an integer from 0 to 4, or is (e) a member of (d) substituted with at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C8 alkyloxy, C1 to C8 haloalkyloxy, C1 to C8 haloalkyl, aryl, and a halogen.
Preferred R2 Substituents:
R2 is preferably selected from the group consisting of hydrogen, C2-C4 alkyl, C2-C4 alkenyl, xe2x80x94Oxe2x80x94(C1-C3 alkyl), xe2x80x94Sxe2x80x94(C1-C3 alkyl), xe2x80x94C3-C4 cycloalkyl xe2x80x94CF3, halo, xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO3. Particularly preferred R2 groups are selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, xe2x80x94F, xe2x80x94CF3, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94Oxe2x80x94CH3.
Preferred R3 Substituents:
A preferred subclass of compounds of formula (I) are those wherein for xe2x80x94(L3)xe2x80x94 Z, Z is represented by 
and X is oxygen.
Another preferred subclass of compounds of formula (I) are those wherein Z is an oxime amide group 
wherein R3 is an oxime amide group and Ra is hydrogen, methyl or ethyl.
Also preferred is a subclass of compounds of formula (I) wherein Z is an acetamide group 
wherein, X is oxygen or sulfur; and Ra is selected from hydrogen, C1-C8 alkyl, aryl, and C1-C8 alkaryl.
For the group R3 it is most preferred that the linking group xe2x80x94(L3)xe2x80x94 be a bond.
Preferred R4 Substituents:
Another preferred subclass of compounds of formula (I) are those wherein, R4 is the group WR4e wherein W is oxygen, and R4e is a non-interfering substituent independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, thiomethyl, C4-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C2-C6 haloalkyl, C1-C6 hydroxyalkyl, xe2x80x94C(O)O(C1-C6 alkyl), xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, xe2x80x94(CONHSO2R), xe2x80x94CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, xe2x80x94(CH2)nxe2x80x94CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiocarbonyl, and carbonyl; where n is from 1 to 8.
Most preferred as non-interfering substituents are hydrogen, methyl, ethyl, propyl, and isopropyl.
Preferred as the N-hydroxyfunctional amide group in the group R4 is the group: 
wherein R4a is selected from the group consisting of OH, (C1-C6)alkoxy and aryloxy; and
wherein R4b is an organic substituent selected from the group consisting of H, C1-C8 alkyl, aryl, C7-C14 aralkyl, C7-C14 alkaryl, C3-C8 cycloalkyl, C1-C8 alkoxyalkyl and these groups substituted with halogen, xe2x80x94CF3, xe2x80x94OH, C1-C8 alkyl, amino, carbonyl, and xe2x80x94CN. A more preferred R4a group is selected from the group consisting of xe2x80x94OH, xe2x80x94OCH3 and xe2x80x94OC2H5. A more preferred R4b is selected from the group consisting of H, C1-C8 alkyl, aryl, C7-C14 aralkyl, C7-C14 alkaryl, C3-C8 cycloalkyl. A most preferred R4b is a group selected from H, CH3, C2H5 and C3H7.
Another preferred subclass of compounds of formula I are those wherein R4 is the group xe2x80x94(Lc)xe2x80x94(acylamino acid group)-, wherein xe2x80x94(Lc)xe2x80x94 is an acylamino acid linker with an acylamino acid linker length of 2 or 3, and the xe2x80x9cacylamino acid groupxe2x80x9d is represented by the formula: 
wherein R4c is selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl and aryl, xe2x80x94CF3; and wherein NR4d is an amino acid residue of either a natural or unnatural amino acid with the nitrogen atom being part of the amino group of the amino acid; and wherein the amino acid residue is derived from an amino acid selected from the group comprising isoleucine, valine, phenylalanine, aspartic acid, leucine, glycine, asparagine, cystein, glutamine, glutamic acid, histidine, lysine, methionine, serine, threonine, tryptophan, tyrosine and derivatives thereof.
Preferred R5 Substituents:
A preferred acid linker, xe2x80x94(La)xe2x80x94, for R5 is selected from the group consisting of; 
wherein R54, R55, R56 and R57 are each independently hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, or halo. Preferred (acidic group) for R5 is selected from the group consisting of xe2x80x94CO2H, xe2x80x94SO3H and xe2x80x94P(O)(OH)2.
Another preferred subclass of compounds of formula (I) are those wherein R5 is a non-interfering substituent, and the non-interfering substituent is independently selected from methyl, ethyl, propyl, isopropyl, thiomethyl, xe2x80x94O-methyl, C4-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C2-C6 haloalkyl, C1-C6 hydroxyalkyl, xe2x80x94C(O)O(C1-C6 alkyl), xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, xe2x80x94(CONHSO2R), xe2x80x94CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, xe2x80x94(CH2)nxe2x80x94CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiocarbonyl, and carbonyl; where n is from 1 to 8.
Most preferred as non-interfering substituents are methyl, ethyl, propyl, and isopropyl.
Preferred compounds of the invention are those having the general formula (II), or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; 
wherein;
R22 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, xe2x80x94F, xe2x80x94CF3, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94Oxe2x80x94CH3; wherein R14 is selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, xe2x80x94(Lc)xe2x80x94 (acylamino acid group), xe2x80x94(Lh)xe2x80x94(N-hydroxyfunctional amide group) or xe2x80x94(La)xe2x80x94(acidic group).
R15 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, and halo.
R13 is selected from hydrogen and C1-C8 alkyl, C1-C8 alkoxy, xe2x80x94Sxe2x80x94(C1-C8 alkyl), C1-C8 haloalkyl, C1-C8, phenyl, halophenyl, hydroxyalkyl, and halo, and t is an integer from 0 to 5.
Also preferred are substituted pyrrole-3-oxime amide compounds of the invention represented by compounds of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof; 
wherein;
A is O, S, or NR, and R is as described previously;
R1, R2, and R5 are as described previously, and
R3 is represented by the group xe2x80x94(L3)xe2x80x94 Z, where xe2x80x94(L3)xe2x80x94 is a divalent linker group selected from a bond or a divalent group selected from: 
xe2x80x83and Z is selected from an oxime amide or oxime thioamide group represented by the formulae, 
xe2x80x83wherein, X is oxygen or sulfur; and Ra is selected from hydrogen, C1-C8 alkyl, aryl, C1-C8 alkaryl, C1-C8 alkoxy, aralkyl and xe2x80x94CN;
R4 is selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, xe2x80x94(Lc)xe2x80x94(acylamino acid group), xe2x80x94(Lh)xe2x80x94(N-hydroxyfunctional amide group) or xe2x80x94(La)xe2x80x94(acidic group).
Also preferred are substituted pyrrole-3-amide compounds of the invention represented by compounds of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof; 
wherein;
A is O, S, or NR, and R is as described previously;
R1, R2, and R5 are as described previously, and
R3 is represented by the group xe2x80x94(L3)xe2x80x94Z, where xe2x80x94(L3)xe2x80x94 is a divalent linker group selected from a bond or a divalent group selected from: 
xe2x80x83and Z is selected from an amide or a thioamide group represented by the formulae, 
xe2x80x83wherein, X is oxygen or sulfur; and Ra is selected from hydrogen, C1-C8 alkyl, aryl, C1-C8 alkaryl, C1-C8 alkoxy, aralkyl and xe2x80x94CN; and n is 0, 1, 2 or 3;
R4 is selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, xe2x80x94(Lc)xe2x80x94(acylamino acid group), xe2x80x94(Lh)xe2x80x94(N-hydroxyfunctional amide group) or xe2x80x94(La)xe2x80x94(acidic group).
21. Preferred specific compounds (and all pharmaceutically acceptable salts, solvates and prodrug derivatives thereof) which are illustrative of the compounds of the invention include compounds represented by the formulae (C1), (C2), (C3), (C4), (C5), (C6), (C7), (C8), (C9), (C10), (C11), (C12), and (C13); 
a pharmaceutically acceptable salt or prodrug derivative thereof.
The salts of the above substituted pyrrole compounds represented by formulae (I) and (II) are an additional aspect of the invention. In those instances where the compounds of the invention possess acidic or basic functional groups various salts may be formed which are more water soluble and physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts, include but are not limited to, the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin.
Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Phar. Sci., 66: 1-19 (1977)). Moreover, the basic group(s) of the compound of the invention may be reacted with suitable organic or inorganic acids to form salts such as acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, chloride, edetate, edisylate, estolate, esylate, fluoride, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, bromide, chloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, malseate, mandelate, mesylate, methylbromide; methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate, pantothenate, phosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, tosylate, trifluoroacetate, trifluoromethane sulfonate, and valerate.
Certain compounds of the invention may possess one or more chiral centers and may thus exist in optically active forms. Likewise, when the compounds contain an alkenyl or alkenylene group there exists the possibility of cis- and trans-isomeric forms of the compounds. The R- and S-isomers and mixtures thereof, including racemic mixtures as well as mixtures of cis- and trans-isomers, are contemplated by this invention. Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. All such isomers as well as the mixtures thereof are intended to be included in the invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art by using stereospecific reactions with starting materials which contain the asymmetric centers and are already resolved or, alternatively by methods which lead to mixtures of the stereoisomers and subsequent resolution by known methods. For example, a racemic mixture may be reacted with a single enantiomer of some other compound. This changes the racemic form into a mixture of diastereomers and diastereomers, because they have different melting points, different boiling points, and different solubilities can be separated by conventional means, such as crystallization.
Prodrugs are derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Derivatives of the compounds of this invention have activity in both their acid and base derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic or aromatic esters derived from acidic groups pendent on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Particularly preferred esters as prodrugs are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, morpholinoethyl, and N,N-diethylglycolamido.
N,N-diethylglycolamido ester prodrugs may be prepared by reaction of the soduium salt of a compound of Formula (I) (in a medium such as dimethylformamide) with 2-chloro-N,N-diethylacetamide (available from Aldrich Chemical Co., Milwaukee, Wis. USA; Item No. 25,099-6).
Morpholinylethyl ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) 4-(2-chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4, 220-3).
a) The substituted pyrrole-3-glyoxylamide derivative compounds of the invention are generally prepared by appending the glyoxylamide group to the 3 position of the substituted pyrrole nucleus (prepared as described infra), generating intermediates which are themselves compounds of the invention. Alternatively, this is followed by coupling the xe2x80x9cacidic groupxe2x80x9d or the xe2x80x9cacylamino acid groupxe2x80x9d or the xe2x80x9cN-hydroxyfunctional amide groupxe2x80x9d at the 4 or 5 position depending on the starting material, to the intermediate above to form other compounds of the invention. Preparation of the 3-glyoxylamide intermediates 7 or 7a is as shown in scheme 1: 
In general, a compound of formula 1 (scheme 1) wherein A is O, NR, SO, SO2, or S is reacted with ethyl azidoacetate. In formula 1 when A is sulfur, the compound 1 is 4-methoxythiophen-3-carbaldehyde (CAS #82069-74-7) and can be synthesized in two steps from the corresponding 4-methoxythiophen-3-carboxylic acid methylester (purchased from Maybridge Chemical Company) using lithiumaluminum hydride reduction to the alcohol, followed by oxidation with for example, TPAP (tetra-n-propylammonium perruthenate(VI)) (CAS#114615-86-9, Aldrich Chemical Co., Milwaukee, U.S.A.) in combination with 4-methylmorpohline-N-oxide in methylene chloride. The use of molecular is sieves in the oxidation of alcohol to aldehyde as above is optional but preferred. The resulting starting material compound (1) is isolated by methods known to one of skill in the art, including but not limited to chromatography, crystallization, or distillation. Other compounds of formula 1 wherein A is NR, SO, or SO2, may be purchased where available or made by methods known to one of skill in the art. The reaction to form compound (2) is catalyzed by a base, preferably a strong base such as sodium ethoxide purchased or generated as needed by dissolving sodium metal in absolute ethanol. The reagents are added at about xe2x88x9220xc2x0 C. and allowed to warm up to about 30-50xc2x0 C. over 30 to 60 minutes. The reaction mixture is worked-up by dilution with water and filtration, or by aqueous extraction as necessary to afford the azidoacrylate compound of formula (2). The compound of formula (2) is ring closed to afford the compound of formula (3) under heating, and preferably in the presence of a catalyst. The preferred reaction conditions include heating compound (2) in refluxing toluene or other suitable solvent in the presence of a catalytic amount of a catalyst, e.g. rhodium acetate dimer. The product substituted pyrrole compound (3) is isolated by concentration followed by recrystallization. Other methods of isolation are within the purview of this invention and are known to one of skill in the art. The compound of formula (3) is transformed to the compound of formula (4) or analog thereof, by reacting compound (3) with an organic halide in the presence of a base such as for example sodium hydride and in the presence of a solvent such for example dimethylformamide. For example, treatment of compound (3) with sodium hydride in DMF followed by addition of benzylbromide results in compound (4) upon work-up. The compound of formula (4) is converted to the ketone, for example, the methylketone. Preparation of compound (5) is accomplished for example, by reaction of compound (4) with xcexc-chloro-xcexc-methylenelbis(cyclopentadienyl)-titanium)dimethylaluminum (Tebbe reagent). The formation of the methylketone derivative using the Tebbe reagent involves addition of about 1.2 molar equivalent of Tebbe reagent to a cold (about 0xc2x0 C.) solution of compound (4) in tetrahydrofuran followed by warming to about room temperature. Upon satisfactory completion of the reaction as determined by common laboratory methods, i.e., HPLC, GC, TLC, GCMS etc, the reaction fixture is quenched by addition of saturated aqueous potassium carbonate. This likely results in vigorous evolution of gas. The product (5) is isolated upon aqueous extractive work up procedures and standard purification methods, i.e. chromatography and/or crystallization.
The compound of formula (5) may be converted to the compound of formula (6) or (6a). The compound of formula (6) may be obtained for example, by use of borane.tetrahydrofuran complex (CAS#14044-65-6, Aldrich Chemical Co.) or other method suitable for the reduction of compound (5) in THF or other suitable solvent or solvent mixture. The compound of formula (6a) may be obtained by the use of mild and/or selective reducing agents and/or reaction conditions which do not affect the methoxy substituent at position 4 or 5 depending on the starting material employed. The compound of formula (6) or (6a) may be reacted with oxalyl chloride followed by reaction with ammonia (THF solution saturated with ammonia) to afford the compound of formula (7) or the corresponding analog compound of formula (7a).
Conversion of the 3-glyoxylamide intermediate to the acidic group derivatives at position 4 or 5 is shown for example in scheme 1A below: 
According to scheme 1A, the compound of formula (7a) may be demethylated for example with boron tribromide in methylene chloride or other suitable solvent to afford the compound of formula (8a). The compound of formula (8a) may be o-acylated, o-alkylated, o-arylated or otherwise converted to a compound represented within the scope of R4. For example reaction of compound (8a) with NaH/mineral oil and a xcex1-bromoalkanoic acid ester e.g. xcex1-bromoethylacetate affords the compound of formula (9a). The compound of formula (9a) may be converted to the free acid (boa) by hydrolysis. The free acid (10a) may in turn be converted to the acid salt or to derivatives such as the ester or amide by procedures known to one of skill in the art or found in general reference texts (J. March Advanced Organic Chemistry, Wiley Interscience publishers, New York, N.Y., 1985, and R. C. Larock Comprehensive Organic Transformations, VCH Publishers, New York, N.Y., 1989). Compounds (7), (7a), (8a), (9a) and (10a) are also compounds contemplated to be within the scope of the present invention.
Functionalization of position 4 or 5 of compound (10a) to the acylamino acid derivative (10c) may be accomplished by room temperature base catalyzed condensation of the amino acid protected at the acid terminus (using a protecting group known in the literature but preferably the methyl ester), with the substituted pyrrole-3-glyoxylamide acid derivative compound of formula (10a) for example. The reaction is accomplished using coupling agents such as HOBT/EDCI, BOP/collidine or other amide bond forming coupling agents. Similarly, the N-hydroxyfunctional amide group may be introduced via the acid (10a) or acid salt thereof, by reaction with for example hydroxylamine hydrochloride or substituted hydroxylamine hydrochloride to afford the N-hydroxyfunctional amide compound of formula (10b).
b) Substituted pyrrole-3-acetamide derivative sPLA2 inhibitors.
Substituted pyrrole-3-acetamide sPLA2 inhibitor derivatives of compounds (6) or (6a) may be lithiated at the (3) position with an organolithium reagent e.g. n-butyllithium, followed by quenching the lithiated intermediate with ethylene oxide for example, to afford upon hydrolysis, the terminal alcohol derivative (10d) at position (3) (scheme 2): 
The resulting alcohol intermediate (10d), itself a compound of the invention may be converted by oxidation to the acid and further converted to the ester (11). Conversion of the alcohol intermediate (10d) to compound ester via an intermediate acid may be accomplished by oxidation of the alcohol with sodium hypochlorite in buffered t-butanol for example, followed by esterification of the incipient acid to the ester (11). Methods for these conversions are known to one of skill in the art and may be found in general reference texts disclosed herein. The ester (11) may be converted to the acetamide derivative (12) or other substituted acetamide compound. For example the reaction of the acetate (11) with methylchloroaluminum amide in benzene or other suitable solvent or solvent mixtures affords the acetamide (compound 12). (See Levin, J. I.; Turos, E.; Weinreb, S. M. An alternative procedure for the aluminum-mediated conversion of esters to amides. Syn.Comm., 1982, 12, 989-993).
Similarly, use of N-substituted methylchloroaluminum amides result in the corresponding substituted acetamides (see Weinreb supra). The 3-substituted amide or acetamide substituted pyrrole compounds described above may be converted to the corresponding 4-substituted acylamino acid compounds or the 4-substituted N-hydroxyfunctional amide compounds as described previously for the glyoxylamide compounds.
c) The substituted pyrrole-3-oxime amide compounds of the invention can be prepared following protocol of scheme 3 below: 
To introduce the oxime functionality, the compound of formula (7), for example, is heated with hydroxylamine hydrochloride (when R is H) in a THF/methanol mixture for about 1 to 8 hours or until the reaction is deemed complete. The reaction product compound (7c), a compound of the invention, is isolated by chromatography or other known laboratory procedure. Substituted oximes such as when R is methyl, ethyl, phenyl or other non-interfering substituent may be prepared by reaction of the corresponding substituted hydroxylamine hydrochloride or free base with the glyoxylamide (e.g. compound 7) as described supra.
Similarly, the ester i.e. methylester of the acid compound (10a), or the acid salts thereof, may be converted to the corresponding oxime or substituted oxime functionality at position (3) by the method described above. The ester functionality at the (4) or (5) position on the substituted pyrrole nucleus, as in for example, compound (13), may be converted to the acid by hydrolysis using lithium hydroxide or other known ester hydrolysis methods to afford a compound of formula (14). See, for example, J. March Advanced Organic Chemistry, Wiley Interscience publishers, New York, N.Y., 1985, and R. C. Larock Comprehensive Organic Transformations, VCH Publishers, New York, N.Y., 1989.
Furthermore, the oxime compounds prepared as described above may be converted to the N-hydroxyfunctional amide at the 4 or 5 position, via the free acid, the ester or the acid salt functionalities at the 4 or 5 position. For example, scheme 3 shows the conversion of the free acid compound (14) to the N-hydroxyfunctional amide compound (15).
Likewise, the compound (14) and analogs thereof may be converted to the acylamino acid compound (16) and corresponding homologs thereof by procedures described supra.
The substituted pyrrole compounds described herein are believed to achieve their beneficial therapeutic action principally by direct inhibition of mammalian (including human) sPLA2, and not by acting as antagonists for arachidonic acid, nor other active agents below arachidonic acid in the arachidonic acid cascade, such as 5-lipoxygenases, cyclooxygenases, and etc.
The method of the invention for inhibiting sPLA2 mediated release of fatty acids comprises contacting mammalian sPLA2 with a therapeutically effective amount of substituted pyrrole compounds corresponding to formulae (I) or (II) as described herein including salt or a prodrug derivative thereof.
Another aspect of this invention is a method for treating Inflammatory Diseases such as inflammatory bowel disease, septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, osteoarthritis, and related diseases which comprises administering to a mammal (including a human) a therapeutically effective dose of the substituted pyrrole compound of the invention (see, formulae I and II).
As previously noted the compounds of this invention are useful for inhibiting sPLA2 mediated release of fatty acids such as arachidonic acid. By the term, xe2x80x9cinhibitingxe2x80x9d is meant the prevention or therapeutically significant reduction in release of sPLA2 initiated fatty acids by the compounds of the invention. By xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The specific dose of a compound administered according to this invention to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration and the condition being treated. Typical daily doses will contain a non-toxic dosage level of from about 0.01 mg/kg to about 50 mg/kg of bodyweight of an active compound of this invention.
Preferably compounds of the invention (per Formula I or II) or pharmaceutical formulations containing these compounds are in unit dosage form for administration to a mammal. The unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these. The quantity of Active ingredient in a unit dose of composition may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration.
The compound can be administered by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
Pharmaceutical formulations of the invention are prepared by combining (e.g., mixing) a therapeutically effective amount of the substituted pyrrole compound of the invention together with a pharmaceutically acceptable carrier or diluent therefor. The present pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.
In making the compositions of the present invention, the Active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), or ointment, containing, for example, up to 10% by weight of the active compound. The compounds of the present invention are preferably formulated prior to administration.
For the pharmaceutical formulations any suitable-carrier known in the art can be used. In such a formulation, the carrier may be a solid, liquid, or mixture of a solid and a liquid. For example, for intravenous injection the compounds of the invention may be dissolved in at a concentration of 2 mg/ml in a 4% dextrose/0.5% Na citrate aqueous solution. Solid form formulations include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
Tablets for oral administration may contain suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, together with disintegrating agents, such as maize, starch, or alginic acid, and/or binding agents, for example, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid, or talc.
In powders the carrier is a finely divided solid which is in admixture with the finely divided Active ingredient. In tablets the Active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about 1 to about 99 weight percent of the Active ingredient which is the novel compound of this invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes, and cocoa butter.
Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs.
The Active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both. The Active ingredient can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol. Other compositions can be made by dispersing the finely divided Active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.
The following pharmaceutical formulations 1 thru 8 are illustrative only and are not intended to limit the scope of the invention in any way. xe2x80x9cActive ingredientxe2x80x9d, refers to a compound according to Formula (I) or (II) or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
The components are blended and compressed to form tablets each weighing 665 mg
The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to xe2x88x9230xc2x0 C. and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
The Active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous solution containing polyvinylpyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50xc2x0 C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
The Active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.
The Active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
The Active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume.
The solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 ml per minute.
All of the products of the Examples described below as well as intermediates used in the following procedures showed satisfactory NMR and IR spectra. They also had the correct mass spectral values. 
To a suspension of lithium aluminum hydride (5.19 g, 137 mmol) in tetrahydrofuran (75 mL) cooled to 0xc2x0 C. was added a solution of 4-methoxythiophene-3-carboxylic acid methyl ester (23.5 g, 137 mmol) in tetrahydrofuran (125 mL) over 15 min. The resulting mixture was stirred at room temperature for 1 h. The solvent volume was doubled with hexane and the resulting mixture treated carefully with 5 N sodium hydroxide solution (10 mL). The resulting mixture was stirred at room temperature for 2 h then filtered. The solids were washed thoroughly with fresh portions of diethyl ether. The combined organic filtrates were dried (sodium sulfate), filtered, and concentrated in vacuo to provide 18.2 g (93%) of the title compound as a pale yellow oil. 1H NMR (CDCl3) xcex4 7.11 (d, J=2 Hz, 1H), 6.23 (d, J=2 Hz, 1H), 4.58 (s, 2H), 3.85 (s, 3H), 2.09 (s, 1H); MS ES+m/e 145 (p+1); IR (CHCl3, cmxe2x88x921) 3603, 3012, 1565, 1478. 
A solution of (4-methoxythiophen-3-yl)methanol (0.370 g, 2.57 mmol) and 4-methylmorpholin-N-oxide (0.328 g, 2.83 mmol) in methylene chloride (5 mL) was treated with tetrapropylammonium perruthenate (5 mg) at room temperature for 2 h Additional portions of 4-methylmorpholin-N-oxide (100 mg) and tetrapropylammonium perruthenate (5 mg) were added and the resulting mixture stirred for 18 h. The. mixture was filtered down a short column of silica gel, which was washed thoroughly with diethyl ether. The combined filtrates were concentrated in vacuo to provide 0.31 g (85%) of the title product as a yellow oil. 1H NMR (CDCl3) xcex4 9.86 (s, 1H), 8.00 (d, J=2 Hz, 1H), 6.25 (d, J=2 Hz, 1H), 3.89 (s, 3H).